S2C5: The Immune System

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a) Immune functions

Somehow the topic of biological immunity has proved one of the most difficult so far to frame and structure for the purpose of these essays. I think the reason is two-fold: firstly there is the diversity in the type of molecular interactions involved, there is detecting, marking, neutralizing, destroying, etc. and secondly there isn’t just one system but several layers each with different functions, some of which are deeply interconnected. Truly, this in an epic and so I have had to resort to the try-and-tested method of abstracting this flurry of processes into broader functions before devoting more time to describe the main actors and their roles in section b).

Before functions, we need to think about purpose. What is our organism trying to achieve through what we conveniently term the immune system? In this case, it is not reproduction or the creation and storage of information, though information does of course play a central role, it is survival.

But what can threaten this survival? Damage to the cells.

How can cells be damaged? By physical impact or chemical interaction from internal or external agents. The former is called an injury, and the latter is essentially what we call disease, defined by the Cambridge Dictionary as “an illness of people, animals, plants, etc., caused by infection or a failure of health rather than by an accident”.

How to address the issue? Prevent the agents from showing up in the first place, recognize them when they do, neutralize or destroy after identifying them, and repair any damage if possible.

Evolution has followed the script and these are indeed the key functions of our immune system: keep out, destroy or neutralize, and heal. Evolution has also leveraged the notion of information to include messaging as a central tool in the entire architecture, it does so by signalling any threat more widely throughout the organism in order to recruit help – a case of force in numbers and efficiency in specialized biomolecules.

The first line of defence against external agents consists in preventing their penetration within the organism by deploying physical and chemical barriers in areas exposed to the outside environment such as our eyes, nose, mouth and throat, i.e. our respiratory tract, as well as our genitalia and of course our entire skin surface. Taking the example of the respiratory tract, this is achieved primarily via the secretion of a thick solution called mucus that shields our tissues from pathogens by trapping them and then either destroying them, such as with antimicrobial enzymes, or mechanically expulsing them. Pathogen is a generic word which encapsulates any agent able to cause a disease though it should be pointed out that non-biological molecules can also be at the origin of diseases, in particular in our industrialized world prone to pollution. The term of “germ” is also sometimes used in lieu of pathogen and the best-known culprits are bacteria and viruses even though not all of them will be harmful to us and some may even turn out to be of assistance and co-opted by our organisms, as in the human microbiome.

In the event the first barrier is breached, or if the enemy (so to speak) is already within, as in the case with cancerous cells, then the immune system needs to be in a position to identify the injury, cells or organisms putting the rest of the organism at risk. Nature could have gone two ways one would think: either endow the actors within our immune system with the capacity to recognize our own cells and treat everything else as pathogen, or the reverse, which is to identify specific pathogens and not take action towards any other body it doesn’t recognize. The latter has the obvious drawback that never-seen before pathogens may spread undetected. The former means having a fully exhaustive catalogue of our internal molecules and neutralize or expunge everything else from the organism, an option which is both highly problematic and unworkable. Problematic because quid of nutrients for instance but more crucially what if the immune system simply has not been able to identify its own cells or macromolecules? Should there be a cut off time in the identification process after which destruction begins? No, this is clearly the wrong evolutionary route for a complex organism and the only default-stance which can be adopted consistently over time and in the context of a broad biochemical environment is to only trigger action upon positive identification. And thus, actors within the immune system come with receptors, a technology we have seen used repeatedly and reliably by our endocrine sub-systems in Series 2 Section 4.a and the very concept of pattern recognition in proteins on the back of the specific shape into which they fold was introduced in S1 Section 4.a.

Unlike the receptors involved in the endocrine systems however, this time around it is the patrolling armada of our immune systems that carries those receptors and may happen to bind to other molecules or part thereof called antigens and the precise bonding site is called epitope. This binding is intermolecular in nature and takes the form of hydrogen bonds or van der Walls forces so it is nowhere as strong as a chemical reaction resulting in an intramolecular binding and, consequently, it is reversible. You may wish to refer to S1 Section 2.d for a better understanding of intermolecular bonding.

Once a pathogen has been identified, three scenarios can play out depending on what type of agent is involved, as well as a combination of those. The first is for the agent to take direct action against it. The second is to mark it for handling by another actor within the system, and this is typically accompanied by the third avenue of calling for reinforcement.

In terms of actions, one option is the neutralization of the pathogen and if we think of a pathogen’s damaging action as a function made possible by an antigen at its surface then the simplest way to negate this function is for the defensive agent from our immune system to bind itself there, essentially disarming the pathogen from the perspective of our organism. If the binding is not on the antigen or doesn’t translate into a neutralization, this mechanism can still be used by our immune system as a marker for further targeting by other actors within our immune system. The second option is destruction by phagocytes, literally “eating cells”. This isn’t as graphic as it sounds at the molecular scale though the consequence is very much the destruction of the pathogen. The technique involves the wrapping of part of a phagocyte’s membrane around the targeted particle followed by the release of highly reactive chemicals and enzymes specializing in breaking down molecules – it is worth clarifying here that the target may be the pathogen itself or a cell it has infected and which it is using for replication. The third option is somewhat similar to the second but skips the enclosing part to directly release packets of enzymes compartmentalized within small vesicles called granules.

The main biomolecules involved in the signalling process once pathogens have been identified and marked up, are proteins called cytokines. These are secreted by various types of cells involved in the immune system and act by binding to receptors on the outside of other cells within the system, thus precipitating a cascade of chemical reactions within those cells. As regulators and carriers of information, their role is partly analogous to that of hormones but the location of their synthesis and domain of action is comparatively much more diffuse.

Once the danger has been dealt with, it is also important for the organism to be in a position to downregulate the immune response in order to avoid continuous inflammation and, quite simply, prevent potential damage to the organism itself from too acute a response. Again, this is similar to the negative feedback loops of the endocrine system, a mechanism introduced in S2 Section 4.b, whereby the number of activated cells will be brought down, including by turning on the programmed-cell-death pathway via apoptosis. Call if friendly-fire if you will. This is all parts and parcel of good homeostasis management but I should highlight that some cells involved in the immune response will be conserved and act as a memory bank. This can make all the difference should an encounter with the same pathogen occur again in the future, a scenario we will discuss in section c).

The word inflammation was mentioned in the previous paragraph and it calls for a proper explanation around the underlying causes and purposes of this physiological phenomenon. Inflammation is sometimes described as a voluntary process of our organism, and certainly the swelling aspect seems to be, but it can also be understood as a symptom of our generic defensive and repair mechanisms in case of injury or immune response to a pathogen. What the organism is trying to achieve is an immediate and initially overwhelming response to address an important threat and does so by boosting the circulation of the agents on which it relies. It does so primarily by increasing blood flow, the number of chemical messengers in circulation and releasing some of the proteins present in the blood plasma in the tissue itself. All this creates a local increase in temperature, redness, pain and swelling. Coagulation may also be brought into the picture to prevent blood loss caused by injury.

b) Lymphatic system & main actors

So far, I have purposely eschewed listing too many names of specialized cells and organs involved in the immune system in order to avoid overwhelming our memory and instead the focus was squarely on thinking through and understanding the most important functions. It is now an opportune time to introduce more actors in the cast within the framework of the lymphatic system which comprises mini-organs and vessels for channelling the lymph.

The lymph is a liquid derived from blood plasma having crossed the capillaries of our blood vessels into tissues throughout our body as part of the diffusion mechanism described in S2 Section 1.d. This interstitial fluid sweeps some waste and possibly pathogens like bacteria and cancerous cells from within our tissues before being brought into the lymphatic vessels, complementary to but different from the blood vessels, by crossing the membrane of the lymph capillaries. During its journey through those channels, the lymph flows through lymph nodes, a collection of small organs measuring on average 15mm in length; there are somewhere around 500 of them in a human body and the only place they can’t be found is in our brain. Their role is sometimes compared to the kidneys for their filtering capability but a military check-point might also be a good analogy.

Indeed, lymph nodes are the main place of residence of lymphocytes who carry out many of the immune activities we described in the previous section, including the detection, neutralization and detection of pathogens. Many of those defensive cells will also flow out of the lymph nodes within the lymph, filtered out of some of the cellular debris and other unwanted particles such as bacteria, which is eventually reabsorbed into the bloodstream, not without carrying some proteins and fats from the digestive system with it.

Lymphocytes, monocytes and the granulocytes together make up what we call the white blood cells, these agents of our immune system that are synthesized in the bone marrow and circulate in our blood. Lymphocytes make up the majority of the immune cells present in the lymph and come in three different forms, each with its own set of properties and modes of action.

T cells move from the bone marrow to the thymus where they complete their development, this is where the letter T comes from. They become activated when their T-cell receptor (“TCR”) binds to an antigen and can either go for the kill themselves, that would the CD8⁺ sub-type also known as “killer T cells”, or arrange for more help by secreting cytokines that will go on to activate some CD8⁺cells as well as memory B cells – this second sub-type is named CD4⁺ or nicknamed “helper T cells” and I will elaborate on the memory aspect in section c) on the adaptive immune system. The third main-subtype is the Regulatory T cells, they are commonly called “suppressor T cells” since their function is to downregulate the activity of effector cells in case the immune system is mistakenly targeting cells from the organism itself, as in autoimmune diseases. This downregulation takes several forms, the main ones being the use of inhibitory cytokines or the triggering of apoptosis. Sometimes there is no halfway house.
B cells also have their own type of receptors called BCRs and those do bind to antigens with much higher specificity than the TCRs. This activation is sometimes facilitated by the helper T cells and it triggers an antibody response. Antibodies are Y-shaped proteins with antigen binding sites called paratopes at the top of each of their two branches. The binding serves the purpose of identifying and neutralizing the precise antigen, to that end there must essentially be a different paratope with a different sequence of amino acids for each antigen epitope, and so there is: our body comprises millions of different antibody versions. Once a B cell is activated, it will multiply and differentiate either into memory B cells or into plasmablasts or plasma cells that will secrete more of the relevant antibody as part of the immune response. As a side note, this is the reason why knowing which antibody is present in high concentration within our body provides reliable information on the antigen that has been detected and therefore the possible nature of the pathogens. Accordingly, it is a common method of medical diagnostic.
Innate lymphoid cells (ILCs) are involved in the regulation of the adaptive and innate immune systems by way of cytokines, unlike the T and B cells they do not have antigen receptors. ILCs are currently divided by science into five group, the best known of which is NK cells where NK stands for “natural killer”, quite the name to carry. NK cells only constitute part of the innate immune system and can act very quickly because they do not rely on antigen-receptor matching; instead they have receptors that can bind to the tail area of antibodies and thus use those markers to direct them to marked and targeted pathogens where they will release cytotoxic substances, typically via degranulation.
Perfect segue to shift our attention to the second form of immune cells found in the lymph: granulocytes. The name originates from the granules contained within their cytoplasm, these vesicles typically contain cytotoxic molecules such as enzymes and antimicrobial peptides. The latter are strings of amino-acid that can kill pathogen, usually either by rendering the membrane permeable on account of their amphipathicity (with both hydrophobic and hydrophilic elements) or by disrupting key processes within the target’s cytoplasm. The main type of granulocytes is called neutrophils, they are phagocytes circulating in the bloodstream and since they belong to the innate immune system, they are among the cells making their way quickly to the required area following chemical markers.

The third form of immune cells, besides the lymphocytes and granulocytes, is called monocytes. After circulating through the blood they end up in our various tissues where they differentiate into macrophages and dendritic cells. The main functions of macrophages are to phagocytose pathogens or aged neutrophils, generally after the latter have fulfilled their task, and to signal other immune cells by secreting cytokines. As for dendritic cells, their role start as detectors within our tissues, playing the role of sentinels as they are sometimes nicknamed. There they may detect pathogens via their receptors and, through various means including phagocytosis, they appropriate the antigen part of the pathogen and then migrate to the lymph nodes where they essentially raise the alarm by presenting this antigen to T cells for further action.

Finally, before concluding this section, there are two more organs within the lymphatic system I think should be mentioned: the thymus and the spleen. The thymus was previously alluded to once as the home of maturing T cells, it is located between our heart and sternum. The purpose of T cell maturation is to ensure these potent agents of our immune systems can effectively recognize pathogens and not prey on the organism’s own cells. This is achieved by presenting a variety of antigens originating both from previous pathogens and from our own cells to the maturing T cells via the major histocompatibility complex (MHC) and then going through a double selection process. Positive selection consists in keeping only the T cells that bind to an antigen on the MHC, and the negative selection results in the elimination of those T cells that did bind to antigens belonging to the organism.

The spleen is nested behind the stomach and its plays several roles, including the recycling of iron found in the red blood cells, the storage of red blood cells and the removal of aged ones. This is made possible because, as part of the immune system secondary organs, it houses monocytes, some of which facilitate the performance of recycling through phagocytosis. The bone marrow is another important player in the immune system, and it has been mentioned earlier, so I will not discuss it further here but will include a link to the Wikipedia entry at the end of this chapter for further personal investigation.

c) Adaptive immunity

Our immune system has evolved many processes to deal with pathogens and injuries resulting in distinct cascades of signalling and other chemical reactions. In jawed vertebrates, including us mammals, evolution has gone one step further and devised a second strategy we call the adaptive or acquired immune system, which relies on previous exposure to a pathogen to mount a specific immune response. By contrast, the default strategy is termed non-specific immune system or innate immune system. To be sure, both are actually sub-systems of our overall immune system – apologies but I am sticking to the jargon terminology – and we have already introduced all relevant actors and most of the relevant mechanisms during the two previous sections.

The innate immune system is generally the first responder, and in plants, fungi and most animal species, the only one. It relies on physical barriers such as mucus, the identification of pathogens, the secretion and circulation of cytokines, the work, synthesis, and cleaning up of antibodies, and the involvement of various types of white blood cells such as NK cells and monocytes.

The adaptive system complements the innate one and relies on a mechanism called immunological memory. If you recall the sequence of events from the time B cells are activated, sometimes with the assistance of helper T cells, most of them will differentiate into antibody-producing cells and the others will remain in circulation in the bloodstream. All else being equal, there would not be any real gain in retaining these legacy B cells but all else is not equal: a B cell with prior exposure to antigen X will undergo some changes and subsequent selection process resulting in an enhanced affinity to antigen X and an ability to proliferate and differentiate much faster into the antibody-producing plasma cells.

This is called the secondary immune response and its strength and efficacy underpins vaccine technology through the controlled exposure of our innate immune system to a given antigen so that it can react way more quickly and decisively against future infection. Since what matters is the exposure to the antigen, vaccines need not involved the full-fledged live pathogen to create the relevant immunological memory.

Note that some species of jawless vertebrates and insects also display some form of adaptative immunity but the process involved is different to the one that has just been described. The differentiation between jawless and jawed vertebrates simply comes down to line of descent and the acquired immune system we are endowed with first evolved half a billion years ago in jawed fish.

d) Immune disfunctions

With so many interlocking mechanisms and variables, the door is wide open for things to go awry, and indeed they occasionally do.

Perhaps the most common, and generally the less problematic scenario, is when some antibodies bind to antigens from non-harmful substances and thus cause an immune reaction called allergy. Those antigens have accordingly been named allergens and can be found in mundane substances like pollen, dust mites and food items such as shellfish or peanuts. After binding to the allergen, the antibody activates various types of granulocytes that do what they usually do and release histamine as part of the inflammatory response designed to help other white blood cells deal with pathogens. This can cause asthma when it occurs in the lungs and can be life threatening in the case of anaphylaxis when histamine stimulates vasodilation which may precipitate a drop of blood pressure, increase the permeability of the blood vessels potentially leading to fluid leakage into other organs such as the lungs, and also cause swelling that may constrict the airways. The emergency treatment is an injection of epinephrine in the muscles on the outer side of the thigh.

Staying with extreme immune responses, sepsis is a very serious and quite often fatal condition caused by an excessive immune response, typically when dealing with a microbial or bacterial infection that triggers a massive cytokine release. Modulation then kicks in as part of the negative feedback loop with a strong immunosuppression while the uncontrolled inflammation leads to strong dilation of blood vessel and thus a significant drop in blood pressure and the leaking of fluids in the lungs. This systemic perfect storm is called septic shock and can result in multiple organ failure, then death.

Immune dysfunctions not only comprise excessive and unwarranted immune responses, they also include insufficient ones. This state of immunodeficiency can be caused by a disease, a drug, malnutrition or can be inherited. In the latter case, mutations or combinations of various dominant or recessive alleles can lead to a wide range of malfunctions, including auto-inflammation and deficiencies or dysfunctions in B and T cells.

When immunodeficiency is caused by external factors, it is qualified as “acquired”. This should ring a bell since the HIV, a virus, is responsible for the condition aptly named AIDS, which stands for acquired immunodeficiency syndrome. HIV is the acronym for human immunodeficiency viruses (there are two species of them), it is sexually transmitted and infects several types of cells in our immune system, in particular helper T cells such as CD4+ and monocytes. In the case of AIDS, the underlying increasing failure of the immune system compromises the ability of the organism to properly defend itself in cases of other infections or cancer.

e) Trivia – Viruses

We have just mentioned a virus and previously did allude to them in Series 1 in the context of discussing the cell, which they lack, as “the fundamental unit of life”. These organisms are often described as being “at the edge of life”, in part because they do have genetic material but are unable to replicate it without a host cell. This goes right at the heart of their role as infectious agents since they do not have their own metabolism and rely on hijacking that of the cell they have penetrated.

A key criteria in the classification of viruses is the way in which they induce a replication of their genome, this can be quite unusual and conveniently they do have their own enzymes to facilitate this process if required – that goes without saying, for otherwise they would not replicate and would have become extinct long ago. For instance, a retrovirus reverses the standard pattern of DNA transcription into RNA, hence the “retro” name, and instead transcribes its RNA into DNA strands that it implants into the DNA of the host who then goes on producing copies, after which virus parts will self-assemble. No magic involved but the process is still a matter of intense study.

From our perspective, viruses can be a real nuisance, an obvious understatement, even though in the majority of cases they are dealt with by our immune system. However, they are also pretty good at evading it and do so by relying on changes in the DNA sequence of the antigens which often translates into a modified shape our antibodies and our memory B cells may not be able to match, undermining their ability to react strongly and quickly.

Variations in virus DNA can be a consequence of antigenic drift or antigenic shift. Antigenic drift arises due to natural genetic mutations and, following the universal evolutionary logic, if this provides a fitness advantage in the form of non-detection by immune systems then this immediate comparative survival rate ensures this mutation will become prevalent as more of the viruses carrying this mutation replicate. Antigenic shift is different in its mechanism, yet similar in its effects; it is caused by the recombination of genetic material from two viruses with different DNA, what we call “strains”, and at the origin of major pandemic, those of the influenza virus in particular. This reassortment, this is the technical term, occurs when a host has been infected by two different strains of the virus and, during the self-assembly process within the host cells, there is some mixing of DNA segments, effectively creating a third strain of the virus.

The most common vectors of viral transmissions are organisms such as insects but they can oftentimes also be airborne in particulate matter. Not without irony, virus themselves are also used as vectors in medical research since their ability to insert their DNA or RNA into a host cell can be leveraged to deliver genetic material in such a cell by essentially altering the virus’ own genetic makeup.

a) Immune functions

b) Lymphatic system & main actors

c) Adaptive immunity

d) Immune disfunctions

e) Trivia – Viruses

f) Further reading (S2C5)